The goal of this research project is to design and develop a new generation of biodegradable macromolecular MRI contrast agents with high kinetic chelation stability for non-invasive evaluation of the efficacy of cancer therapies. Timely and accurate assessment of cancer treatments is critical for achieving the best possible therapeutic outcomes and improving the survival of cancer patients and the quality of their lives. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) can quantitatively measure the changes of tumor physiology before any morphological changes can be observed. In this research project, we propose to design and develop polydisulfides containing macrocyclic Gd(III) chelates as a new generation of biodegradable macromolecular MRI contrast agents and to explore their applications in tumor imaging and non-invasive assessment of the efficacy of anticancer therapies. The macrocyclic Gd(III) chelates have shown high thermodynamic and kinetic chelation stability against transmetallation with endogenous ions and excrete intact from the body. The novel biodegradable macromolecular MRI contrast agents will have an improved safety profile and provide more accurate assessment of therapeutic efficacy with DCE-MRI. The specific aims of the project are 1) to design, synthesize and characterize polydisulfides containing macrocyclic Gd(III) chelates of high kinetic chelation stability as a new generation of biodegradable macromolecular MRI contrast agents; 2) to evaluate the relaxivities, degradability and kinetic chelation stability of the novel polydisulfide Gd(III) complexes; 3) to investigate in vivo kinetic stability of the Gd(III) chelates, in vivo degradation, pharmacokinetics, clearance and long-term tissue accumulation of the synthesized new biodegradable macromolecular contrast agents in animal models; 4) to investigate the effectiveness of the novel biodegradable macromolecular contrast agents in cancer imaging with conventional and dynamic contrast enhanced MRI and in non-invasive assessment of the therapeutic efficacy of anti-HIF-11 RNAi for cancer therapy in animal tumor models. Our long-term goal is to develop safe effective biodegradable macromolecular contrast agents with high kinetic chelation stability for accurate non-invasive assessment of the efficacy of anticancer therapies with DCE-MRI.